HCV was cloned and characterized about 15 years ago by Choo and colleagues (see Science 244, (1989), 359-362). HCV belongs to the family Flaviviridae and comprises an enveloped nucleocapsid and a single-stranded RNA genome of positive polarity (see Bartenschlager et al., Antiviral Res. 60, (2003), 91-102). HCV is transmitted primarily by blood, blood products and vertical transmission during pregnancy. Introduction of diagnostic tests for screening blood products has significantly reduced the rate of new infection.
Still, HCV remains a serious medical problem. There are currently about 170 million people infected with HCV. The initial course of infection is typically mild. However, the immune system is often incapable of clearing the virus, and people with persistent infections are at a high risk for liver cirrhosis and hepatocellular carcinoma (see Poynard et al., Lancet 349, (1997), 825-832).
There is no vaccine available, and therapeutic options are very limited (see Manns et al., Indian J. Gastroenterol. 20 (Suppl. 1), (2001), C47-51; Tan et al., Nat. Rev. Drug Discov. 1, (2002), 867-881).
Compounds which bind strongly to cyclophilin have been identified but those compounds were immunosuppressive (Nakagawa M et al., Biochemical and biophysical research communications, Academic Press Inc. Orlando, Fla., US, Vol. 313, No 1, 2 Jan. 2004, pages 42-47, XP004479114).
Therefore, during the last 20 years, a number of medicinal chemistry studies have been conducted with the aim to identify non-immunosuppressive compounds such as NIM 811 or other compounds presenting also a high potency to inhibit HIV-1 replication and essentially lacking of immunosuppressive activity, see WO 00/01715 (Wenger et al.; DEBIOPHARM SA) and Tetrahedron Lett., 41, (2000), 7193-6.
It has been found that non-immunosuppressive compounds which bind to cyclophilin have an inhibitory effect on Hepatitis C virus (HCV). Persistent infection by HCV, which has been identified as the major causative agent of non-A, non-B hepatitis has been considered closely related to liver diseases such as chronic hepatitis, liver cirrhosis or hepatocellular carcinoma. The development of these liver diseases is a major public health problem. Effective anti-HCV therapy is restricted to therapy with interferon or a combination of interferon and ribavirin. However, since the virus is not eliminated from about a half of the HCV patients treated with these known agents, there is still a strong need for alternative anti-HCV agents.
Cycloundecapeptides having the property to act on inhibition of hepatitis C virus (HCV) replication are already known from WO 2005/021028 (Novartis Pharma GMBH) and WO 2006/038088 (DEBIOPHARM SA). Hanssons M J et al. Journal of Bioenergetics and biomembranes, plenum publishing, New York, N.Y., US, Vol. 36, no 4, 1 Aug. 2004, pages 407-413 (XP002330699) reports the better potencies of mPT inhibition by the compounds described in WO 2006/038088. However although some of these peptides are presently involved in clinical trials, there is still a need to develop new antiviral agents having satisfactory property to inhibit the replication of, in particular, HCV, along with improved pharmacokinetic profile (e.g. hepatic transporter inhibition profile and resulting drug-drug interactions) and with improved toxicology profile (e.g. non-immunosuppressive activity, and resulting adverse events).
Accordingly, the present invention aims to provide further non-immunosuppressive compounds to be used in the prevention or treatment of Hepatitis C infections or HCV induced disorders. Those compounds have the unexpected advantage either to reduce the potential adverse effects related to the inhibition of hepatic transporters or the potential drug-drug interactions related to the inhibition of hepatic transporters or even both. In addition it is also an object of the invention to provide compounds that are easier to synthesize in particular at an industrial scale.